Method of hypertensive treatment using phenyl-alkylene-2-pyridyl derivatives

ABSTRACT

Compounds of the formulae: ##STR1## wherein, Z and Y are each alkylene or oxy-alkylene containing one to about five carbon atoms in the principal chain or said alkylene substituted with OH, alkanoyloxy, alkoxy, mercapto or alkylmercapto; 
     each of R 1 , R 2  and R 3  is independently H, alkyl, aryl, halo, alkoxy, alkenyloxy, alkylsulfinyl, alkylsulfonyl, alkylmercapto, cyano, carboxy, carbalkoxy, carboxamido, sulfamoyl, trifluoromethyl, hydroxy, hydroxyalkyl, acyloxy, alkylamino, sulfonylamino, or acylamino; or R 1  and R 2 , when taken together, form a methylenedioxy or --O--CO--O--; 
     Ar is heteroaryl, cycloalkyl or ##STR2##  wherein, R 1 , R 2  and R 3  are as hereindescribed; and R is H, alkyl, cycloalkyl, aryl, aralkyl, alkenyl, alkynyl, carboalkoxy, or CONR 4  R 5  wherein each of R 4  and R 5  is H or alkyl; wherein the total number of carbon atoms in each hydrocarbyl group is up to 10; and ##STR3##  wherein, each of R 1  and R 2  is independently H, alkyl, aryl, halo, alkoxy, alkenyloxy, alkylsulfinyl, alkylsulfonyl, alkylmercapto, cyano, carboxy, carbalkoxy, carboxamido, sulfamoyl, trifluoromethyl, hydroxy, hydroxyalkyl, acyloxy, alkylamino, sulfonylamino, or acylamino; or R 1  and R 2 , when taken together, form a methylenedioxy, or --O--CO--O--; R 6  is H, alkyl, aryl, halo, alkoxy, alkenyloxy, alkylsulfonyl, alkylmercapto, cyano, carboxy, carbalkoxy, carboxamido, sulfamoyl, trifluoromethyl, hydroxy, hydroxyalkyl, acyloxy, alkylamino, sulfonylamino or acylamino; wherein the total number of carbon atoms in each hydrocarbyl group is up to 10; and acid addition salts thereof have selective cardiotonic, antihypertensive and antiallergic activity.

This application is a division of copending application Ser. No.692,602, filed Jan. 17, 1985, issued as U.S. Pat. No. 4,569,941 on Feb.11, 1986, which in turn is a continuation of application Ser. No.477,460, filed Mar. 21, 1983, now abandoned.

This invention relates to new pharmaceutically-active compounds and moreparticularly to certain new cyclic amines possessing usefulpharmaceutical activities, especially selective cardiotonic activity,anti-hypertensive activity and anti-allergic activity.

Pharmaceutically-active amines of the formula: ##STR4## wherein R ishydrogen or alkyl have been described in German Patent Specification No.2,317,710. These compounds are reported to have cardiotonic activity.

The new compounds of the present invention are cyclic amines of theformulae: ##STR5## wherein,

Z and Y are each alkylene or oxy-alkylene containing one to about fivecarbon atoms in the principal chain or said alkylene substituted withOH, alkanoyloxy, alkoxy, mercapto or alkylmercapto;

each of R₁, R₂ and R₃ is independently H, alkyl, aryl, halo, alkoxy,alkenyloxy, alkylsulfinyl, alkylsulfonyl, alkylmercapto, cyano, carboxy,carbalkoxy, carboxamido, sulfamoyl, trifluoromethyl, hydroxy,hydroxyalkyl, acyloxy, alkylamino, sulfonylamino, or acylamino; and R₁and R₂, when taken together, form a methylenedioxy or --O--CO--O--;

Ar is heteroaryl, cycloalkyl, alkyl or ##STR6## wherein, R₁, R₂ and R₃are as hereindescribed; and

R is H, alkyl, cycloalkyl, aryl, aralkyl, alkenyl, alkynyl, carboalkoxy,or CONR₄ R₅ wherein each of R₄ and R₅ is H or alkyl; and acid additionsalts thereof.

The total number of carbon atoms in each such hydrocarbyl substituentcan range up to about 10. The substituent "Z" contains up to about 5carbons in the principal chain, i.e., the straight chain of carbonsbetween the terminal valences, but can be branched in that methyl andethyl substituents can be present on the principal chain. Thus, the Zchain can contain a total number of carbon atoms greater than 5,preferably no more than about 8.

Heteroaryl as employed herein refers to any heterocyclic structure inwhich at least one of 0, S and N are present as the hetero atoms. Theseinclude thiophene, furan, pyridine, thiazole, pyrimidine, pyrrole,benzofuran, quinoline, benzothiophene and substituted heterocycles.

The preferred compounds are those in which the hydrocarbyl radicalscontain up to about 7 carbon atoms when aliphatic and up to about 10carbon atoms aromatic, e.g., phenyl, tolyl and naphthyl.

The particularly preferred compounds are cyclic amines of the formulae:##STR7## wherein, R₁ and R₂ are as previously defined; and R₆ is H,alkyl, aryl, halo, alkoxy, alkenyloxy, alkylsulfonyl, alkylmercapto,cyano, carboxy, carbalkoxy, carboxamido, sulfamoyl, trifluoromethyl,hydroxy, hydroxyalkyl, acyloxy, alkylamino, sulfonylamino or acylamino;and acid addition salts thereof.

In particular, the preferred compounds are of the structure ##STR8##wherein R₁, R₂ and R₆ are hydroxy or alkanoyloxy and may be the same ordifferent, the alkyl portion in the alkanoyloxy having up to 6 carbonatoms.

As should be apparent to those skilled in the art, the present newcompounds exist in isomeric forms due to the spatial arrangement ofsubstituents at the positions ortho to the nitrogen atom in the cyclicamine, i.e., cis and trans forms; and can also exist in the form ofoptical isomers when there are asymmetric centers, e.g., as insubstituents Z and Y. The present new compounds include all of theisomeric forms, in particular, the cis, trans-isomers, both of which canbe present in the products as produced by the synthetic process selectedfor preparation. The mixtures of isomers are useful as are theindividual, i.e., separated, isomers for therapy.

The present new compounds are readily preparable by art-recognizedprocedures. A particularly effective procedure involves reduction of thecorresponding new dehydro-cyclic amines of the formulae: ##STR9##wherein, R₁, R₂, R₃, Z, Y and Ar are as previously defined. Of course,substituents susceptible of reduction under the process conditions canbe converted to their corresponding reduction product, e.g., nitro toamino.

The new intermediate compounds of formulae V and VI can also be preparedby art-recognized methods. The following reaction sequence employingpyrrolidine derivatives is exemplary: ##STR10##

Each of the steps of the foregoing sequence is accomplished using knownprocedures as described in the examples which follow. The hydrogenationstep to convert compounds of formulae V and VI to correspondingcompounds of formulae I and II can be accomplished using any of theknown processes for reducing an ethylenic double bond. The most commonand facile of these is catalytic hydrogenation, e.g., over noble metalcatalysts such as palladium or platinum catalysts. Such catalytichydrogenations are normally effected at superatmospheric pressures ofhydrogen gas, e.g., 3 to 20 atmospheres, until the theoretical uptake ofhydrogen has occurred. For efficiency, the hydrogenation is carried outin a solvent such as tetrahydrofuran, dioxane and the like.

The compounds wherein R is other than hydrogen may be prepared from thecompounds where R is hydrogen by standard technique for the alkylationor acylation of an amine.

Of particular value are the compounds wherein R₁ and R₂ are acyloxy.These compounds are preferably prepared from the compounds wherein R₁and R₂ are methoxy by the following sequence of reactions: ##STR11##

Methods for the preparation of other compounds of the present inventionare outlined below: ##STR12##

Employing the foregoing procedures, a variety of new pyrrolidine andpiperidine compounds of formulae I and II can be prepared:

    __________________________________________________________________________    Z      R    Y   R.sub.1                                                                           R.sub.2  R.sub.3   Ar                                     __________________________________________________________________________    CHCH.sub.3                                                                           CH.sub.3                                                                           C.sub.2 H.sub.4                                                                   H   H        H         C.sub.6 H.sub.5                        CHCH.sub.3                                                                           CH.sub.3                                                                           C.sub.2 H.sub.4                                                                   H   CH.sub.3 H         C.sub.6 H.sub.5                        CH.sub.2 CH.sub.2                                                                    CH.sub.3                                                                           C.sub.2 H.sub.4                                                                   H   H        H         C.sub.6 H.sub.4 Cl                     CH(CH.sub.3)CH.sub.2                                                                 C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.4                                                                   H   H        Cl        C.sub.6 H.sub.4 CH.sub.3               CH.sub.2 CH.sub.2                                                                    CH.sub.3                                                                           i-C.sub.3 H.sub.6                                                                 H   CN       H         C.sub.4 H.sub.3 S                      CH.sub.2 CH.sub.2                                                                    CH.sub.3                                                                           C.sub.2 H.sub.4                                                                   H   H        NO.sub.2  C.sub.4 H.sub.3 O                      CH.sub.2 CH.sub.2                                                                    CH.sub.3                                                                           C.sub.2 H.sub.4                                                                   H   OH       H         C.sub.5 H.sub.4 N                      CH.sub.2 CH.sub.2                                                                    C.sub.3 H.sub.7                                                                    CH.sub.2                                                                          H   H        CF.sub.3  C.sub.3 H.sub.2 NS                     CH(CH.sub.3)                                                                         C.sub.4 H.sub.9                                                                    C.sub.2 H.sub.4                                                                   H   OCH.sub.3                                                                              H         C.sub.6 H.sub.5 CH.sub.2               (CH.sub.2).sub.3                                                                     C.sub.6 H.sub.13                                                                   C.sub. 2 H.sub.4                                                                  H   COOH     H         C.sub.6 H.sub.5                        CH.sub.2 CH.sub.2                                                                    i-C.sub.4 H.sub.9                                                                  CH.sub.2                                                                          OCH.sub.3                                                                         H        H         ClC.sub.6 H.sub.4                      CH.sub.2 CH.sub.2                                                                    H    C.sub.2 H.sub.4                                                                   H   OCH.sub.3                                                                              OCH.sub.3 MeOC.sub.6 H.sub.4                     (CH.sub.2).sub.5                                                                     C.sub.6 H.sub.5 CH.sub.2                                                           C.sub.2 H.sub.4                                                                   H   CH.sub.3 CH.sub.3  C.sub.6 H.sub.4 OH                     CH.sub.2 CH.sub.2                                                                    C.sub.6 H.sub.11                                                                   C.sub.2 H.sub.4                                                                   H   H        CH.sub.2 C.sub.6 H.sub.5                                                                C.sub.6 H.sub.4 OH                     CH.sub.2 CH.sub.2                                                                    H    C.sub.2 H.sub.4                                                                   H   H        C(CH.sub.3).sub.3                                                                       C.sub.6 H.sub.4 OH                     CH(CH.sub.3)CH.sub.2                                                                 C.sub.6 H.sub.5                                                                    C.sub.2 H.sub.4                                                                   H   H        C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.4 OH                     CH.sub.2                                                                             H    C.sub.2 H.sub.4                                                                   H   H        H         C.sub.6 H.sub.4 OH                     CH.sub.2                                                                             H    C.sub.2 H.sub.4                                                                   Cl  Cl       Cl        C.sub.6 H.sub.4 OH                     CH.sub.2                                                                             H    C.sub.2 H.sub.4                                                                   Cl  H        Cl        C.sub.6 H.sub.4 OH                     CH.sub.2                                                                             H    C.sub.2 H.sub.4                                                                   Cl  H        OH        C.sub.6 H.sub.4 OH                     CH.sub.2                                                                             H    C.sub.2 H.sub.4                                                                   OCH.sub.3                                                                         H        CH.sub.2CHCH.sub.2                                                                      C.sub.6 H.sub.4 OH                     CH.sub.2                                                                             H    C.sub.2 H.sub.4                                                                   H   H        H         C.sub.6 H.sub.4 OCH.sub.3              CHOH   H    C.sub.2 H.sub.4                                                                   H   CH.sub.3 H         C.sub.6 H.sub.4 OCH.sub.3              CHOH   H    C.sub.2 H.sub.4                                                                   OH  OH       H         C.sub.6 H.sub.4 OCH.sub.3              CHOH   H    C.sub.2 H.sub.4                                                                   H   H        H         C.sub.6 H.sub.4 OCH.sub.3              CHSH   H    C.sub.2 H.sub.4                                                                   H   CH.sub.3 H         C.sub.6 H.sub.4 OCH.sub.3              CHOCH.sub.3                                                                          H    C.sub.2 H.sub.4                                                                   H   CH.sub.3 CH.sub.3  C.sub.6 H.sub.4 OCH.sub.3              CHSCH.sub.3                                                                          H    C.sub.2 H.sub.4                                                                   H   H        H         C.sub.6 H.sub.4 OCH.sub.3              CHOH   H    C.sub.2 H.sub.4                                                                   H   H        H         C.sub.6 H.sub.4 OCH.sub.3              CHOCOCH.sub.3                                                                        H    C.sub.2 H.sub.4                                                                   H   CH.sub.3 H         C.sub.6 H.sub.4 OCH.sub.3              CH.sub.2 CH.sub.2                                                                    H    C.sub.2 H.sub.4                                                                   H   H        Cl        C.sub.6 H.sub.3 (OH).sub.2             CH.sub.2 CH.sub.2                                                                    H    C.sub.2 H.sub.4                                                                   H   CN       H         C.sub.6 H.sub.3 (OH).sub.2             CH.sub.2 CH.sub.2                                                                    H    C.sub.2 H.sub.4                                                                   NO.sub.2                                                                          H        H         C.sub.6 H.sub.3 (OH).sub.2             CH.sub.2 CH.sub.2                                                                    H    C.sub.2 H.sub.4                                                                   H   OH       H         C.sub.6 H.sub.4 OH                     CH.sub.2 CH.sub.2                                                                    H    C.sub.2 H.sub.4                                                                   H   CF.sub.3 H         C.sub.6 H.sub.4 OH                     CH.sub.2 CH.sub.2                                                                    H    C.sub.2 H.sub.4                                                                   H   OCH.sub.3                                                                              H         C.sub.6 H.sub.4 OH                     CH.sub.2 CH.sub.2                                                                    H    C.sub.2 H.sub.4                                                                   H   COOH     H         C.sub.6 H.sub.4 OH                     CH.sub.2 CH.sub.2                                                                    H    C.sub.2 H.sub.4                                                                   OCH.sub.3                                                                         H        H         C.sub.6 H.sub.4 OH                     CH.sub.2 CH.sub.2                                                                    H    C.sub.2 H.sub.4                                                                   H   OCH.sub.3                                                                              OCH.sub.3 C.sub.6 H.sub.4 OH                     CH.sub.2 CH.sub.2                                                                    H    C.sub.2 H.sub.4                                                                   H   H        OCH.sub.3 C.sub.6 H.sub.4 OH                     CH.sub.2 CH.sub.2                                                                    H    C.sub.2 H.sub.4                                                                   OCH.sub.3                                                                         H        CH.sub.2CHCH.sub.2                                                                      C.sub.6 H.sub.4 OH                     CH.sub.2 CH.sub.2                                                                    H    C.sub.2 H.sub.4                                                                   H   H        COOCH.sub.3                                                                             C.sub.6 H.sub.4 OH                     CH.sub.2 CH.sub.2                                                                    H    C.sub.2 H.sub.4                                                                   OCH.sub.3                                                                         H        COOCH.sub.3                                                                             C.sub.6 H.sub. 4 OH                    CH.sub.2 CH.sub.2                                                                    H    C.sub.2 H.sub.4                                                                   H   OH       CH.sub.2 OH                                                                             C.sub.6 H.sub.4 OH                     CH.sub.2 CH.sub.2                                                                    H    C.sub.2 H.sub.4                                                                   H   H        NH.sub.2  C.sub.6 H.sub.4 OH                     CH.sub.2                                                                             H    C.sub.2 H.sub.4                                                                   H                                                                                  ##STR13##                                                                              ##STR14##                                                                               ##STR15##                             CH.sub.3                                                                             H    C.sub.2 H.sub.4                                                                   H   OH       SOCH.sub.3                                                                              C.sub.6 H.sub.4 OH                     CHOH   H    C.sub.2 H.sub.4                                                                   H   OH       SOCH.sub.3                                                                              C.sub.6 H.sub.3 (OCH.sub.2 O)          CHOH   H    C.sub.2 H.sub.4                                                                   H   OH       CONH.sub.2                                                                              C.sub.6 H.sub.3 (OCH.sub.2 O)          CHOH   H    C.sub.2 H.sub.4                                                                   H   OH       CH.sub.2 OH                                                                             C.sub.6 H.sub.4 OH                     CH.sub.2                                                                             H    C.sub.2 H.sub.4                                                                   H   OH       NHSO.sub.2 CH.sub.3                                                                     C.sub.6 H.sub.4 OH                     CHOH   H    C.sub.2 H.sub.4                                                                   H   OH       NHSO.sub.2 CH.sub.3                                                                     C.sub.6 H.sub.4 OH                     __________________________________________________________________________

The present new cyclic amines are therapeutically useful as such or canbe employed in the form of salts in view of their basic nature. Thus,these compounds form salts with a wide variety of acids, inorganic andorganic, including therapeutically-acceptable acids. The salts withtherapeutically-acceptable acids are, of course, useful in thepreparation of formulations where water solubility is desired. The saltswith therapeutically-unacceptable acids are particularly useful in theisolation and purification of the present new compounds. Therefore, allacid salts of the present new compounds are contemplated by the presentinvention.

The pharmaceutically-acceptable acid addition salts are of particularvalue in therapy. These include salts of mineral acids such ashydrochloric, hydriodic, hydrobromic, phosphoric, metaphosphoric,nitric, sulfuric acids, as well as salts of organic acids such astartaric, acetic, citric, malic, benzoic, glycolic, gluconic, succinic,arylsulfonic, e.g., p-toluenesulfonic acids, and the like. Thepharmaceutically-unacceptable acid addition salts, while not useful fortherapy, are valuable for isolation and purification of the newsubstances. Further, they are useful for the preparation ofpharmaceutically-acceptable salts. Of this group, the more common saltsinclude those formed with hydrofluoric and perchloric acids.Hydrofluoride salts are particularly useful for the preparation of thepharmaceutically-acceptable salts, e.g., the hydrochlorides, by solutionin hydrochloric acid and crystallization of the hydrochloride saltformed. The perchloric acid salts are useful for purification andcrystallization of the new products.

As therapeutic agents, the present new heterocyclic compounds showpotent selective cardiotonic activities. In addition, these compoundsare also useful as anti-hypertensive agents and anti-allergic agents.The therapeutic agents of this invention may be administered alone or incombination with pharmaceutically-acceptable carriers, the proportion ofwhich is determined by the solubility and chemical nature of thecompound, chosen route of administration and standard pharmaceuticalpractice. For example, they may be administered orally in the form oftablets or capsules containing such excipients as starch, milk, sugar,certain types of clay and so forth. They may be administered orally inthe form of solutions which may contain coloring and flavoring agents orthey may be injected parenterally, that is, intramuscularly,intravenously or subcutaneously. For parenteral administration, they maybe used in the form of a sterile solution containing other solutes, forexample, enough saline or glucose to make the solution isotonic.

The physician will determine the dosage of the present therapeuticagents which will be most suitable and it will vary with the form ofadministration and the particular compound chosen, and furthermore, itwill vary with the particular patient under treatment. He will generallywish to initiate treatment with small dosages substantially less thanthe optimum dose of the compound and increase the dosage by smallincrements until the optimum effect under the circumstances is reached.It will generally be found that when the composition is administeredorally, larger quantities of the active agent will be required toproduce the same effect as a smaller quantity given parenterally. Thecompounds are useful in the same manner as comparable therapeutic agentsand the dosage level is of the same order of magnitude as is generallyemployed with these other therapeutic agents. The therapeutic dosagewill generally be from 10 to 750 milligrams per day and higher althoughit may be administered in several different dosage units. Tabletscontaining from 10 to 250 mg. of active agent are particularly useful.

The following examples further illustrate the invention.

EXAMPLE 1 Preparation of dehydro compounds (Formulae V and VI) A.1-(3,4-Dimethoxyphenyl)-2-nitroethene

In a 1 l. r.b. flask 100 g. (0.6 mole) of 3,4-dimethoxybenzaldehyde, 40g. (0.52 mole) of ammonium acetate, 50 ml. (0.93 mole) of nitromethane,and 400 ml. of glacial acetic acid were combined and refluxed for 2hours. The solution was then cooled to room temperature overnight.Yellow crystals were then collected via suction filtration and washedwith hexane and ether. 73 g. of desired product were collected with m.p.133°-134° C.

1-(3,4-Dimethoxyphenyl)-nitroethane

To a 1 l. 3-necked r.b. flask equipped with mechanical stirrer andthermometer, and cooled in an icewater bath 32 g. (0.847 mole) of NaBH₄pellets and 300 ml. of ethanol were added. The reaction solution wasstirred and cooled to 3° C. before the portionwise addition of 21 g.(0.1 mole) of 1-(3,4-dimethoxyphenyl)-2-nitroethene was started. Thenitro alkene was added at such a rate as to keep the temperature of thereaction less than 13° C. The resulting solution was stirred anadditional 30 min. at ice bath temperature upon the completion ofaddition.

The foamy solution was then poured into 400 ml. of ice-cold 10% NH₄ Clsolution and stirred until the effervesence had subsided. This solutionwas filtered and concentrated in vacuo to remove the ethanol.Crystallization of 1-(3,4-dimethoxyphenyl)-2-nitroethane occured in theaqueous solution, or the oily product was extracted with ether (3×250ml.), dried over anhydrous MgSO₄ and concentrated to give 20 g. ofcrystalline product with m.p. 47°-50°.

C. 4-Methoxybenzyl bromide

To a cold solution of 138.17 g. (1 mole) of 4-methoxybenzyl alcohol in1000 ml. of dry ether was added dropwise 135.35 g. (0.5 mole) ofphosphorus tribromide keeping temperature below 10° C. After addition ofPBr₃ was completed, the mixture was stirred at room temperature for onehour and 30 min. The resulting reaction solution was poured intoicewater with agitation, and the product was extracted with ether, whichwas dried over anhydrous MgSO₄ and anhydrous potassium carbonate. Uponremoving ether in vacuo, a slightly pinkish crude product was distilledat 89°-90° C./0.15 mm./Hg. yielding 186 g. of 4-methoxybenzyl bromide.

D. Ethyl 4-(4-Methoxybenzyl)acetoacetate

Into a 3 l. 3-necked r.b. flask equipped with a mechanical stirrer,thermometer, dropping funnel, and nitrogen gas inlet was placed 24 g.(0.5 mole) of 50% NaH prewashed with hexane, and 1000 ml. of drytetrahydrofuran. 65 g. (0.5 mole) of ethyl acetoacetate was then addeddropwise at -10° to 0° C. using a dry ice-acetone bath. After additionof ethyl acetoacetate was finished, the mixture was gradually warmed upto 10° C. in the course of 15 minutes and then 240 ml. (0.528 mole) of2.2M n-butyllithium was added dropwise maintaining temperature below-40° to -20° C. After the mixture was stirred at -10° for 15 minutes,100.5 g. (0.5 mole) of 4-methoxybenzyl bromide was added dropwise over aperiod of 45 minutes at -10° C. The reaction mixture was graduallywarmed up to room temperature and stirred for an additional hour, andthen cooled to -20° C. 5N HCl was then carefully added until thesolution was slightly acidic.

The product was extracted with ether several times and ether layer wasdried over anhydrous MgSO₄. After the solvent was distilled, the crudeproduct was used for the next reaction without purification.

E. Ethyl 5-(4-Methoxyphenyl)-3,3-ethylenedioxypentanoate

The above crude keto ester was ketallized with 100 ml. of ethyleneglycol, 2 g. of p-toluenesulfonic acid, and 800 ml. of benzene using aDean-Stark Trap until no more water was separated. The cooled reactionmixture was poured into a cold dilute NaHCO₃ solution and extracted withether several times. The combined ether layer was backwashed with wateronce, and dried over anhydrous MgSO₄. The product was distilled at155°-167° C./0.25 mm Hg. to give 97 g. of ketal ester.

F. 3,3-Ethylenedioxy-5-(4-methoxyphenyl)-1-pentanol

Into a 2 l. 3-necked r.b. flask equipped with mechanical stirrer, refluxcondenser, and heating mantle was added 18 g. (0.474 mole) of LiAlH₄ and500 ml. of dry tetrahydrofuran at such a rate as to control vigorousreflux of reaction solution. 97 g. (0.33 mole) of ethyl5-(4-methoxyphenyl)-3,3-ethylenedioxypentanoate in 100 ml. of drytetrahydrofuran and added dropwise over a period of 40 minutes. Thereaction mixture was stirred at room temperature for 30 minutes andrefluxed for 2 hrs. Excess LiAlH₄ was carefully decomposed withsaturated Na₂ SO₄ solution. The inorganic solid was filtered off andwashed with ethyl acetate. The filtrate was concentrated in vacuoleaving 84.6 g. of crude ketal alcohol.

G. 3,3-Ethylenedioxy-5-(4-methoxyphenyl)-1-pentyl methanesulfonate

A solution of 65.9 g. (0.262 mole) of crude ketal alcohol in 250 ml. ofpyridine was cooled in an ice bath. 60 g. (0.524 mole) ofmethanesulfonyl chloride was added dropwise. The mixture was stirred atice bath temperature for 30 minutes, then for one hour at roomtemperature, and poured into ice containing 200 ml. of conc. HCl. Thepinkish white solid was collected by filtration, washed with cold water,and dried under vacuum at room temperature to leave 89.8 g. of mesylcompound.

H. 1-Iodo-5-(4-methoxyphenyl)-3-pentanone

A mixture of 89.8 g. (0.272 mole) of mesylated derivative, 122.4 g.(0.816 mole) of sodium iodide, and 1000 ml. of acetone was refluxed for2 hours with stirring. The resulting mixture was poured into 2 l. ofwater containing 10 g. of sodium sulfite. The light yellowish solid wasfiltered; washed with water, and dried in vacuum to give 75 g. ofproduct which melts at 38°-42° C.

I. 1-(3,4-Dimethoxyphenyl)-7-(4-methoxyphenyl)-2-nitro-5-heptanone

To a solution of 15 g. (0.071 mole) of2-(3,4-dimethoxyphenyl)-1-nitroethane in 200 ml. of dry tetrahydrofuranwas added 33.45 g. (0.08 mole) of 40% Triton B at room temperature. Thesolution was stirred at room temperature for 14 minutes under N₂. 22.6g. (0.071 mole) of 1-iodo-5-(4-methoxyphenyl)-3-pentanone was then addedin portions. The mixture was heated at 50°-55° for 2 hours under N₂until no more starting material was detected on TLC, and then cooled toroom temperature. The resulting reaction solution was poured into colddil. HCl and extracted with ethyl acetate. The organic layer was driedover anhydrous MgSO₄. The crude material was chromatographed on Florisilto provide 22 g. of desired nitro ketone derivative. Recrystallizationfrom 80% ethanol gave a white solid which has m.p. 87°-89° C.

J. 1-(3,4-Dimethoxyphenyl)-5,5-ethylenedioxy-7-(4-methoxyphenyl)-2-nitroheptane

Into a 1 l. r.b. flask equipped with a Dean-Stark trap was placed 22 g.(0.055 mole) of1-(3,4-dimethoxyphenyl)-7-(4-methoxyphenyl)-2-nitro-5-heptanone, 2 g. ofp-toluenesulfonic acid, 25 ml. of ethylene glycol, and 500 ml. ofbenzene, the mixture was refluxed until no more water was separated, andthen cooled to room temperature. The dark solution was poured into colddil. NaHCO₃ solution and extracted with ethyl acetate. The organic layerwas backwashed with water and dried over anhydrous MgSO₄. Upon removingsolvent by distillation a gray solid was obtained from trituration withether. Recrystallization from 80% ethanol yielded 25 g. of product as awhite solid; m.p. 98°-100° C.

K.2-Amino-1-(3,4-dimethoxyphenyl)-5,5-ethylenedioxy-7-(4-methoxyphenyl)heptane

To a suspension of 6.6 g. (0.174 mole) of LiAlH₄ in 200 ml. of drytetrahydrofuran was added dropwise a solution of 25 g. (0.058 mole) of1-(3,4-dimethoxyphenyl)-5,5-ethylenedioxy-7-(4-methoxyphenyl)-2-nitroheptanein 100 ml. of dry THF at room temperature at such a rate as to controlreflux of reaction solution. After addition of substrate was completed,the reaction mixture was refluxed under N₂ for 2 hours, and cooled toice bath temperature. The excess LiAlH₄ was decomposed with saturatedNa₂ SO₄ solution. The inorganic salt was filtered off and thoroughlywashed with ethyl acetate and chloroform. The filtrate was concentratedin vacuo to give 28 g. of brown, oily product. Without furtherpurification, the amino ketal derivative was used for the next reaction.

L. 2-(3,4-Dimethoxybenzyl)-5-[2-(4-methoxyphenyl)ethyl]-Δ⁵-dehydropyrrolidine

A mixture of 28 g. (0.07 mole) of crude2-amino-1-(3,4-dimethoxyphenyl)-5,5-ethylenedioxy-7-(4-methoxyphenyl)heptaneand 12 g. of p-toluenesulfonic acid in 250 ml. of regulartetrahydrofuran was stirred at room temperature for 12 hours under N₂.The resulting reaction solution was poured into cold dil. NaHCO₃solution and extracted with ethyl acetate several times. The organiclayer was dried over anhydrous MgSO₄. The solvent was removed in vacuoto provide 23 g. of brown, oily product which was purified on adry-column using CHCL₃ -EtOAc (1:1) as the eluent.

EXAMPLE 2 Production of cyclic amines (Formulae I and II) A. A mixtureof 2,5-cis andtrans-2-(3,4-dimethoxybenzyl)-5-[2-(4-methoxyphenyl)ethyl]pyrrolidinehydrochloride

Reduction of 23 g. (0.065 mole) of2-(3,4-dimethoxybenzyl)-5-[2-(4-methoxyphenyl)ethyl]-Δ⁵-dehydropyrrolidine in 200 ml. of methanol was carried out in a Parrhydrogenator in the presence of 670 mg. of PtO₂ and 40 ml. of ethanolichydrogen chloride at 65 psi over 2 days. The catalyst was removed on aCelite bed. Upon removing the solvent in vacuo, 19 g. of gray productwas obtained from ethyl acetate as the hydrochloride salt; m.p.156°-161° C.

B. Cis-2-(3,4-dihydroxybenzyl)-5-[2-(4-hydroxyphenyl)ethyl]pyrrolidinehydrobromide

To a cold solution of 3 g. (0.008 mole) ofcis-2-(3,4-dimethoxybenzyl)-5-[2-(4-methoxyphenyl)ethyl]pyrrolidinehydrochloride in 50 ml. of methylene chloride was added dropwise 8 g.(0.032 mole) of boron tribromide at -60° C. After addition of borontribromide was finished, the cold bath was removed, and the reactionmixture was gradually warmed up to room temperature over a period ofabout one and a half hours. The mixture was then cooled again in DryIce-acetone bath and 25 ml. of methanol was carefully added. Aftermethanol was completely removed, the residue was treated with ethylacetate. Upon storing in a freezer, an off-white solid crystallized out,which was recrystallized from ethyl acetate and ethanol to give 3.11 g.of pure product, m.p. 195°-198° C.

C. Trans-2-(3,4-dihydroxybenzyl)-5-[2-(4-hydroxyphenyl)ethyl]pyrrolidinehydrobromide

A solution of 1 g. (0.003 mole) oftrans-2-(3,4-dimethoxybenzyl)-5-[2-(4-methoxyphenyl)ethyl]pyrrolidinehydrochloride in 35 ml. of methylene chloride was cooled to -65° C. andtreated with 2.68 g. (0.012 mole) of boron tribromide dropwise. Thereaction mixture was then stirred under N₂ and slowly warmed from -65°to room temperature over the course of one hour and 25 minutes. Thesolution was then cooled again to -60° C. and 25 ml. of methanol wascautiously added. Solvent was removed in vacuo, more methanol was addedand some insoluble material was filtered off. After removal of methanolin vacuo, the residue was treated with ethyl acetate. Upon standing atroom temperature, 0.8 g. of product was obtained as an off-white solid,m.p. 202°-203° C.

EXAMPLE 31-(3,'4'-Dimethoxyphenyl)-2-nitro-7-(4'-methylphenyl)-3-heptanoneethylene ketal

In a 500 mL rb flask, 200 mL cyclohexane, 50 mL benzene, 15 g (0.242mole) ethylene glycol, 1.5 g p-toluenesulfonic acid and 19 g (0.049mole) of 1-(3,4-dimethoxyphenyl)-2-nitro-7-(4-methylphenyl)-5-heptanonewere combined and refluxed 24 hours with a Dean-Stark trap. The cooledreaction mixture was poured into cold, sat'd. NaHCO₃ and extracted withthree 200 mL portions of ethyl acetate. The organic layer was dried overMgSO₄, filtered and concentrated. The residue was triturated with etherand ethyl acetate to give some solid (1.5 g) of mp 89°-91° C.

The remaining residue was chromatographed on silica gel usinghex-ether-EtOAc (5:2.5:25). An oily product (15.7 g), still impure wasobtained.

EXAMPLE 41-(3',4'-Dimethoxyphenyl)-2-amino-7-(4'-methylphenyl)-5-heptanoneethylene ketal

In a 500 mL 3 necked rb flask equipped with a mechanical stirrer,condensor and addition funnel, a THF solution of1-(3,4-dimethoxyphenyl)-2-nitro-7-(4-methyphenyl)-5-heptanone ethyleneketal (15.7 g; 0.037 mole) was added slowly to a suspension of LiAlH₄(14.2 g; 0.111 mole) in dry THF. The reaction was refluxed for 2 hours.Excess LiAlH₄ was then decomposed with sat. Na₂ SO₄, the salts filteredand the organic layer dried over MgSO₄, filtered and concentrated toyield 14.2 g of a brown oil.

EXAMPLE 5 2-(3',4'-Dimethoxybenzyl)-5-(2-[4'-methylphenyl]ethyl)-Δ¹(5)-pyrroline

The above 1-(3,4-dimethoxyphenyl)-2-amino-7-(4-methylphenyl)-5-heptanoneethylene ketal (14.2 g; 0.0356 m), 7.5 g p-toluenesulfonic acid and 100mL THF were combined and stirred 24 hours at room temperature undernitrogen. The reaction was poured cautiously into 200 mL cold, sat'dNaHCO₃ and extracted with three 200 mL portions of ethyl acetate. Theorganic layer was dried over MgSO₄, filtered and concentrated.Chromatography of the crude brown oil on silica gel using CHCl₃ :ethylacetate (1:1) gave 7.0 g (0.0188 m) of a brown oil.

EXAMPLE 62-(3',4'-Dimethoxybenzyl)-5-(2-[4'-methylphenyl]ethyl)pyrrolidine

2-(3'4'-dimethoxybenzyl)-5-(2-[4-methylphenyl]ethyl)-Δ¹(5) -pyrroline (7g; 0.0188 moles) was hydrogenated in a Parr shaker with PtO₂ (0.300 g)in 50 mL methanol at 65 psi.

The catalyst was filtered through Celite and the methanol concentrated.The residue was then tritutrated with ethyl acetate and di-isopropylether. Upon standing 2.4 g (0.0064 mole) of a grey solid was obtained.

EXAMPLE 72-(3',4'-Dihydroxybenzyl)-5-(2-[4'-methylphenyl]ethyl)pyrrolidinehydrobromide

In a 100 mL rb flask equipped with magnetic stirrer and addition funnel,2-(3',4'-dimethoxybenzyl)-5-(2-[4'-methylphenyl]ethyl)pyrrolidine (2.4g; 0.0064M) was dissolved in CH₂ Cl₂ and cooled to -70° C. Borontribromide (0.024 mole; 6 g) was added cautiously dropwise and thereaction warmed slowly to room temperature over 2.5 h. under N₂. Thereaction was cooled again to -70° and methanol was added very cautiouslyuntil fuming subsided. The solution was then concentrated in vacuo andthe residue treated with ethyl acetate. Crystallization occurred uponstanding, mp 164°-167°.

EXAMPLE 8 1-(3',4'-dimethoxyphenyl)-7-phenyl-2-nitro-5-heptanone

To a solution of 36 g (0.17 mole) of2-(3,4-dimethoxyphenyl)-1-nitroethane in 300 mL of dry tetrahydrofuranwas added 71 g (0.17 mole) of 40% Triton B. The solution was stirred atroom temperature for 10 min. 55.3 g (0.19 mole) of1-iodo-5-phenyl-3-pentanone in a minimum amount of dry tetrahydrofuranwas added dropwise. The mixture was stirred at room temperature for 30min, at 50° C. for 3 hr., then allowed to stir at room temperatureovernight. Solvent was removed in vacuo and the residue taken up inether and extracted twice with water. The organic layer was dried overanh MgSO₄, and concentrated at reduced pressure to give 71.5 g of crudeoil. This crude material was passed through HPLC to give 46.4 g. ofpurified material.

EXAMPLE 9 1-(3',4'-dimethoxyphenyl)-7-phenyl-2-nitro-5-heptanoneethylene ketal

Into a 1 l r.b. flask equipped with a Dean Stark trap was placed 46.4 g(0.12 m) of 1-(3',4'-dimethoxyphenyl)-7-phenyl-2-nitro-5-heptanone, 1.5.g p-toluenesulfonic acid, 50 mL of ethylene glycol and 300 mL ofcyclohexane. The mixture was allowed to reflux overnight, thenconcentrated in vacuo. Dil NaHCO₃ solution was added to the residue andextracted with ethyl acetate. The organic layer was backwashed withwater, dried over anh. MgSO₄, filtered and concentrated under reducedpressure to give 45.3 g of an oil which solidified on drying at roomtemperature under vacuum.

EXAMPLE 10 2-Amino-1-(3',4'-dimethoxyphenyl)-7-phenyl-5-heptanoneethylene ketal

To a suspension of 12.4 g (0.33 mole) of LiAlH₄ in 500 mL of drytetrahydrofuran was added dropwise a solution of 45.3 g (0.11 mole) of1-(3',4'-dimethoxyphenyl)-7-phenyl-2-nitro-5-heptanone ethylene ketal ina minimum amount of dry tetrahydrofuran. After the addition, thereaction mixture was refluxed gently for 2 hours. The excess LiAlH₄ wasdecomposed with saturated Na₂ SO₄ solution. The inorganic salts werefiltered off and washed with ether. The organic layer was extractedtwice with water, dried over anh. MgSO₄, filtered, and concentratedunder reduced pressure to 250 mL. This was used in the next step.

EXAMPLE 11 2-(3',4'-dimethoxybenzyl)-5-(2-phenethyl)-Δ¹(5) pyrroline

To the above 250 ml solution of crude2-amino-1-(3',4'-dimethoxyphenyl)-7-phenyl-5-heptanone ethylene ketalwas added 38 g of p-toluenesulfonic acid. The solution was stirred undera nitrogen atmosphere overnight. The resulting solution was pouredslowly into dil NaHCO₃ solution and extracted with ether-ethyl acetate.The organic layer was extracted twice with H₂ O, dried over anh. MgSO₄,filtered and concentrated under reduced pressure to give 29.2 g. Thecrude material was further purified by HPLC to give 18.4 g oil.

EXAMPLE 12 2-(3',4'-Dimethoxybenzyl)-5-(2-phenylethyl)pyrrolidine

To a suspension of 10.8 g (0.28 mole) of LiAlH₄ in 500 ml of drytetrahydrofuran was added dropwise a solution of 18.4 g (0.057 mole) of2-(3',4'-dimethoxybenzyl)-5-(2-phenylethyl)-Δ¹(5) pyrroline in a minimumamount of dry tetrahydrofuran. After the addition, the reaction mixturewas refluxed gently for 8 h. The excess LiAlH₄ was decomposed withsaturated Na₂ SO₄ solution. The inorganic salts were filtered off andwashed with ethyl acetate. The organic layer was extracted twice with H₂O, dried over anh. MgSO₄, filtered and concentrated under reducedpressure to give 15.1 g oil.

EXAMPLE 13 2-(3',4'-Dihydroxybenzyl)-5-(2-phenylethyl)pyrrolidinehydrobromide

To a cold (-70° C.) solution of 15.1 g (0.057 mole) of2-(3'4'-dimethoxybenzyl)-5-(2-phenylethyl)pyrrolidine in 1 L ofmethylene chloride was added dropwise 55.1 g (0.22 mole) of borontribromide. After the addition the reaction mixture was gradually warmedup to room temperature over a period of 2 h. The mixture was cooledagain to -70° C. and 300 ml. of methanol was carefully added. Solventwas removed in vacuo. An additional 100 ml of methanol was added andremoved in vacuo. The gummy dark residue was boiled in ethyl acetate anddecanted, then triturated with ethyl acetate and left overnight to givea solid. This was recrystallized twice from acetonitrile to give 6 g.m.p. 149°-151° C.

EXAMPLE 141-(3',4'-Dimethoxyphenyl)-7-(4'-fluorophenyl)-2-nitro-5-heptanone

To a solution of 48.5 g (0.23 mole) of2-(3',4'-dimethoxyphenyl)-1-nitroethane in 400 ml of dry tetrahydrofuranwas added 96.0 (0.23 mole) of 40% Triton B. The solution was stirred atroom temperature for 10 minutes. 66.7 g (0.23 mole) of1-iodo-5-(4'-fluorophenyl)-3-pentanone in a minimum amount of drytetrahydrofuran was added dropwise. The mixture was heated at 50° C. for3 hours, then allowed to stir at room temperature overnight. Solvent wasremoved in vacuo and the residue taken up in ether and extracted twicewith water. The organic layer was dried over anh MgSO₄, filtered andconcentrated at reduced pressure to obtain a crude oil. The crudematerial was passed through HPLC to give 79 g purified material.

EXAMPLE 151-(3',4'-Dimethoxyphenyl)-7-(4'-fluorophenyl)-2-nitro-5-heptanoneethylene ketal

Into a 1 l. r.b. flask equipped with a Dean-Stark trap was placed 79 g(0.2 mole) of1-(3',4'-dimethoxyphenyl)-7-(4'-fluorophenyl)-2-nitro-5-heptanone, 38 gp-toluenesulfonic acid, 120 ml ethylene glycol and 400 ml cyclohexane.The mixture was allowed to reflux overnight, then concentrated in vacuo.Dil NaHCO₃ solution was added to the residue and extracted withmethylene chloride. The organic layer was backwashed with water, driedover anh MgSO₄, filtered and concentrated under reduced pressure toobtain 84.8 g of oily product.

EXAMPLE 162-Amino-1-(3',4'-dimethoxyphenyl)-7-(4'-fluorophenyl)-5-heptanoneethylene ketal

To a suspension of 22.0 g (0.58 mole) of LiAlH₄ in 400 ml of drytetrahydrofuran was added dropwise a solution of 84.8 g (0.2 mole) of1-(3',4'-dimethoxyphenyl)-7-(4'-fluorophenyl)-2-nitro-5-heptanoneethylene ketal in a minimum amount of dry tetrahydrofuran. After theaddition the reaction mixture was refluxed gently for 2 hours. Theexcess LiAlH₄ was decomposed with saturated Na₂ SO₄ solution. Theinorganic salts were filtered off and washed with ether. The organiclayer was extracted twice with water, dried anh MgSO₄, filtered andconcentrated under reduced pressure to 250 ml. This was used in the nextstep.

EXAMPLE 17 2-(3',4'-Dimethoxybenzyl)-5-[2-(4'-fluorophenyl)ethyl]-Δ¹(5)pyrroline

To the above 250 ml solution of crude2-amino-1-(3',4'-dimethoxyphenyl)-7-(4'-fluorophenyl)-5-heptanoneethylene ketal was added 114 g of p-toluenesulfonic acid. The solutionwas stirred under a nitrogen atmosphere overnight. The resultingsolution was poured slowly into dil NaHCO₃ solution and extracted withmethylene chloride. The organic layer was extracted twice with waterdried over anh MgSO₄, filtered and concentrated under reduced pressure.The crude material was further purified by passing through HPLC to give32.5 g of product.

EXAMPLE 182-(3',4'-Dimethoxybenzyl)-5-[2-(4'-fluorophenethyl)]pyrrolidine

To a suspension of 18 g (0.47 mole) of LiAlH₄ in 400 ml of drytetrahydrofuran was added dropwise a solution of 32.5 g (0.095 mole) of2-(3',4'-dimethoxybenzyl)-5-[2-(4'-fluorophenyl)ethyl]-Δ¹(5) pyrrolinein a minimum amount of dry tetrahydrofuran. After the addition, thereaction mixture was refluxed gently for 2 hours. The excess LiAlH₄ wasdecomposed with saturated Na₂ SO₄ solution. The inorganic salt wasfiltered off and washed with tetrahydrofuran and ether. The organiclayer was extracted twice with H₂ O, dried over MgSO₄, filtered andconcentrated under reduced pressure to give 31.48 g.

EXAMPLE 192-(3',4'-Dihydroxybenzyl)-5-[4'-fluorophenyl)ethyl]pyrrolidinehydrobromide

To a cold (-70° C.) solution of 31.4 (0.091 mole) of2-(3',4'-dimethoxybenzyl)-5-[4'-fluorophenyl)ethyl]pyrrolidine in 600 ccof methylene chloride was added dropwise 45.8 g (0.18 mole) of borontribromide. After the addition, the reaction mixture was graduallywarmed to room temperature over a period of 2 hours. The mixture wascooled again to -70° C. and 300 ml of methanol was carefully added.Solvent was removed in vacuo. An additional 100 ml of methanol was addedand removed in vacuo. The gummy dark residue was boiled in ethyl acetateand decanted, then triturated with ethyl acetate and left in therefrigerator overnight to give a solid. After recrystallization from aminimum amount of isopropanol this gave 9.05 g, mp 186°-188° C.

EXAMPLE 201-(3',4'-Dimethoxyphenyl)-7-(4'-chlorophenyl)-2-nitro-5-heptanone

To a solution of 48.5 g (0.23 mole) of2-(3,4-dimethoxyphenyl)-1-nitroethane in 400 ml of dry tetrahydrofuranwas added 96.0 g (0.23 mole) of 40% Triton B. The solution was stirredat room temperature for 10 min. 70.3 g (0.23 mole) of5-iodo-1-(4'-chlorophenyl)-3-pentanone in a minimum amount of drytetrahydrofuran was added dropwise. The mixture was heated at 50° C. for3 hr., then allowed to stir at room temperature overnight. Solvent wasremoved in vacuo and the residue taken up in ether and extracted twicewith water. The organic layer was dried over anh MgSO₄, filtered andconcentrated at reduced pressure. The crude concentrate was passedthrough HPLC to give 65 g of purified material.

EXAMPLE 211-(3',4'-Dimethoxyphenyl)-7-(4'-chlorophenyl)-2-nitro-5-heptanoneethylene ketal

Into 1 l. r.b. flask equipped with a Dean Stark trap was placed 65 g(0.16 mole) of1-(3',4'-dimethoxyphenyl)-7-(4'-chlorophenyl)-2-nitro-5-heptanone, 2 gp-toluenesulfonic acid, 100 ml ethylene glycol and 400 ml ofcyclohexane. The mixture was allowed to reflux overnight, thenconcentrated in vacuo. Dil NaHCO₃ solution was added to the residue andextracted with methylene chloride. The organic layer was backwashed withwater, dried over anh MgSO₄, filtered and concentrated under reducedpressure to obtain 45.3 g of an oil which solidified on drying at roomtemperature under vacuum.

EXAMPLE 222-Amino-1-(3',4'-dimethoxyphenyl)-7-(4'-chlorophenyl)heptan-5-oneethylene ketal

To a suspension of 16.5 g (0.43 mole) of LiAlH₄ in 500 ml of drytetrahydrofuran was added dropwise a solution of 65 g (0.14 mole) of1-(3',4'-dimethoxyphenyl)-7-(4'-chlorphenyl)-2-nitroheptan-5-oneethylene ketal in a minimum amount of dry tetrahydrofuran. After theaddition the reaction mixture was refluxed gently for 2 hrs. The excessLiAlH₄ was decomposed with saturated MgSO₄ solution. The inorganic saltswere filtered off and washed with ether. The organic layer was extractedtwice with water, dried over anh MgSO₄, filtered and concentrated underreduced pressure to 250 ml. This was used in the next step.

EXAMPLE 23 2-(3',4'-Dimethoxybenzyl)-5-(2-(4-chlorophenyl)ethyl)-Δ¹(5)pyrroline

To the above 250 ml solution of crude2-amino-1-(3,4-dimethoxyphenyl)-7-(4-chlorophenyl)-5-heptanone ethyleneketal was added 5.7 gms of p-toluenesulfonic acid. The solution wasstirred under a nitrogen atmosphere overnight. The resulting solutionwas poured slowly into dil NaHCO₃ solution and extracted with methylenechloride. The organic layer was extracted twice with H₂ O, dried overanh MgSO₄, filtered and concentrated under reduced pressure. The crudematerial was further purified by passing through HPLC to give 26.2 gm.

EXAMPLE 242-(3',4'-Dimethoxybenzyl)-5-(2-(4-chlorophenyl)ethyl)pyrrolidine

To a suspension of 13.9 g (0.36 mole) of LiAlH₄ in 400 ml of drytetrahydrofuran was added dropwise a solution of 26.2 g (0.073 mole) of2-(3',4'-dimethoxybenzyl)-5-[2-(4-chlorophenyl)ethyl]-Δ¹(5) -pyrrolinein a minimum amount of dry tetrahydrofuran. After the addition thereaction mixture was refluxed gently for 2 hours. The excess LiAlH₄ wasdecomposed with saturated Na₂ SO₄ solution. The organic salt wasfiltered off and washed with tetrahydrofuran and ether. The organiclayer was extracted twice with H₂ O, dried over MgSO₄, filtered andconcentrated under reduced pressure to give 24.2 g.

EXAMPLE 252-(3',4'-Dihydroxybenzyl)-5-[2-(4-chlorophenyl)ethyl]pyrrolidinehydrobromide

To a cold (-70° C.) solution of 24.2 g (0.67 mole) of2-(3',4'-dimethoxybenzyl)-5-[2-(4-chlorophenyl)ethyl]pyrrolidine in 600cc of methylene chloride was added dropwise 46.5 g (0.186 mole) of borontribromide. After the addition the reaction mixture was gradually warmedto room temperature over a period of 2 hours. The mixture was cooledagain to -70° C. and 300 ml of methanol was carefully added. Solvent wasremoved in vacuo. An additional 100 ml of methanol was added and removedin vacuo. The gummy residue was boiled in ethyl acetate and decanted,then triturated with ethyl acetate and left in the refrigeratorovernight to give a solid. After recrystallization from a minimum amountof methanol there was obtained 7.05 g.

EXAMPLE 262-(3',4'-Dimethoxybenzyl)-5-[2-(4'-methoxyphenethyl)]-1-benzylpyrrolidine

To a solution of2-(3',4'-dimethoxybenzyl)-5-[2-(4'-methoxyphenthkyl)]pyrrolidinehydrochloride in 50 ml dry tetrahydrofuran and 25 ml drydimethylformamide was added 0.96 g (0.02 mole) of 50% NaH. The reactionmixture was heated at 60° C. for 4 hours. 1.71 g (0.01 mole) of benzylbromide was added slowly. After the addition the reaction was heated at50° C. for 2 hours, then stirred overnight. Solvent was removed in vacuoand the residue taken up in methylene chloride and extracted twice withH₂ O. The organic layer was dried over anh MgSO₄, filtered andconcentrated at reduced pressure to give 4.4 g of crude material.

EXAMPLE 271-Benzyl-2-(3',4'-dihydroxybenzyl)-5-[2-(4'-hydroxyphenyl)ethyl]pyrrolidinehydrobromide

To a cold (-70° C.) solution of 4.4 g (0.01 mole) of2-(3',4'-dimethoxybenzyl)-5-[4'-methoxyphenyl)ethyl]-1-benzylpyrrolidinein 100 ml methylene chloride was added dropwise 10 g (0.04 mole) ofboron tribromide. After the addition the reaction mixture was stirred at-70° C. for 1 hour then at room temperature for 1.5 hours. The mixturewas cooled again to -70° C. and 100 cc of methanol was carefully added.Solvent was removed in vacuo. The residue was redissolved in 30 ml ofethyl acetate-acetone and concentrated. Further drying under high vacuumgave 4.4 g of crude solid.

EXAMPLE 282-(3',4'-bis-[3,3-Dimethylbutyryloxy]benzyl)-5-[2-(4'-[3,3-dimethylbutyryloxy]phenyl)ethyl]-1-benzylpyrrolidine

To a solution of 4.0 g (0.008 mole) of2-(3',4'-dihydroxybenzyl)-5-[2-(4'-hydroxyphenyl)ethyl]-1-benzylpyrrolidinehydrobromide in 50 ml pyridine was added dropwise 4 g (0.03 mole) of3,3-dimethylbutyryl chloride. After the addition, the reaction mixturewas stirred at room temperature for 1 hour, then at 70° C. for 1.5hours, and finally at room temperature overnight. The salt was filteredand solvent was removed in vacuo. The residue was taken up in methylenechloride and extracted twice with dil NaHCO₃ solution. The organic layerwas dried over anh MgSO₄, filtered and concentrated at reduced pressure.The crude material was further purified by HPLC to give 2 g.

EXAMPLE 292-(3',4'-bis[3,3-Dimethylbutyryloxy]benzyl)-5-[2-(4'-[3,3-dimethylbutyryloxy]phenyl)ethyl]pyrrolidine

A mixture of 2 g (0.0028 mole) of2-(3',4'-bis[3,3-dimethylbutyryloxy]benzyl)-5-[2-(4'-[3,3-dimethylbutyryloxy]phenyl)ethyl]-1-benzylpyrrolidineand 0.2 g 10% Pd/C in 100 ml methanol was hydrogenated at 60 psi in aParr hydrogenator overnight. This catalyst was filtered off and thefiltrate concentrated under reduced pressure to give 1.7 g. The crudematerial was purified by HPLC to give 0.93 g thick oil.

EXAMPLE 30 2-(4'-Hydroxybenzyl)-5-[2-(4'-methoxyphenyl)ethyl]pyrrolidine

A mixture of 11 g (0.027 mole) of[2-(4'-benzyloxy]benzyl)-5-[2-(4'-methoxyphenyl)ethyl]pyrrolidine and0.5 g 10% PdC in 200 ml of methanol was hydrogenated at 45 psi in a Parrhydrogenator for 48 hours. The catalyst was filtered off and thefiltrate was concentrated under reduced pressure to give 7.6 g crudematerial.

EXAMPLE 31 2-(4'-Hydroxybenzyl)-5-[2-(4'-hydroxyphenyl)ethyl]pyrrolidinehydrobromide

To a cold (-70° C.) solution of 2 g (0.006 mole) of2-(4'-hydroxybenzyl)-5-[2-4'-methoxyphenyl)ethyl]pyrrolidine in 150 mlof methylene chloride was added dropwise 2.5 g (0.01 mole) of borontribromide. After the addition the reaction mixture was stirred at -70°C. for 1 hour, then at room temperature for 1 hour. The mixture wascooled again to -70° C. and 50 ml of methanol was carefully added.Solvent was removed in vacuo. The residue was triturated with 30 mlethyl acetate which was decanted. The residue was again triturated with30 ml acetone to give a solid which was recrystallized from a minimumamount of ethanol to give 560 mg, mp 177°-179° C.

EXAMPLE 32A 2-(3,4-Dimethoxybenzoyl)-6-methylpyridine

To an ice-cooled, stirred suspension of 6-methylpicolinic acid chlorideand 2 equivalents of aluminum chloride in tetrachloroethane is addedslowly an equivalent amount of 1,2-dimethoxybenzene. The reactionmixture is allowed to come to room temperature overnight, thendecomposed over cracked ice. Extractive workup followed bychromatography of the organic residue gives the desired ketone.

EXAMPLE 32B2-(3,4-Dimethoxybenzoyl)-6-(2-(4-methoxyphenyl)ethyl)piperidine

The above ketone is condensed with anisaldehyde using the generalprocedure of Galiazzo, GAZZ. CHIM. ITAL., 95, 1322, (1965).Chromatography of the basic material gives the desired stilbazole.

The stilbazole is dissolved in glacial acetic acid and hydrogenated overAdams' catalyst at 2-3 atm until four equivalents of hydrogen have beenabsorbed. The reaction is filtered, concentrated, and washed withaqueous base to remove the last traces of acetic acid. Chromatographyover silica gel then gives the desired piperidine.

EXAMPLE 32C2(α-Hydroxy-3,4-dimethoxybenzyl)-6-(2-(4-methoxyphenyl)ethyl)piperidine

The above amino ketone is dissolved in ethanol, cooled in ice, andtreated with one equivalent of sodium borohydride. Upon appearance ofstarting material (TLC) the reaction is diluted with water and extractedwith ethyl acetate. The extracts are washed with water, dried, andconcentrated. Fractional crystallization of the derived hydrochloridegives the major diastereomer.

EXAMPLE 33A2-(3,4-Dimethoxybenzyl)-6-(2-(4-methoxyphenyl)ethyl)piperidine

The amino alcohol of Example 32C is dissolved in ethanol andhydrogenated over 10% Pd-C until no further uptake occurs. The solutionis then filtered, concentrated, and chromatographed to give the titletrimethoxy compound.

EXAMPLE 33B2-(3,4-Dimethoxybenzyl)-6-(2-(4-hydroxyphenyl)ethyl)piperidinehydrobromide

The above trimethoxy compound is treated with BBr₃ in the manner of Ex.2. Evaporation of boron compounds and trituration of the residue asdescribed gives the desired salt.

EXAMPLE 342(α,3,4-Trihydroxybenzyl)-6-(2-(4-hydroxyphenyl)ethyl)piperidinehydrobromide

The trimethoxy alcohol of Ex. 32C is treated with excess BBr₃ indichloromethane as described in Ex. 2. Evaporation of boron compoundswith methanol and trituration of the non-volatile material gives thetitle salt.

EXAMPLE 35A (6-Methyl-1-carbobenzyloxy-2-piperidyl)oxirane

A solution of 2-methyl-6-ethenyl-1-piperidyl benzyl urethane inmethylene chloride is cooled to 0° C. and treated with one equivalent ofm-chloroperoxybenzoic acid. After stirring at room temperature untildisappearance of starting material the peracid is decomposed with sodiumbisulfite and the mixture washed with aqueous Na₂ CO₃. The product isused directly.

EXAMPLE 35B 2-Methyl-6-(2-(4-fluorophenyl)oxy-1-hydroxyethyl)piperidine

A solution of a p-fluorophenol in t-butanol is treated with oneequivalent of potassium t-butoxide, followed by the compound of Example35A. The reaction mixture is then refluxed until all epoxide hasreacted. The reaction is cooled, diluted with water, and extracted withethyl acetate. The organic extracts are dried and concentrated. Thecarbobenzyloxy protecting group is removed by standard hydrogenolysisand the final product purified by chromatography.

Using the procedures of Examples 1, 2, 32 and 33, the following cyclicamines of Formulae I and II are prepared from the corresponding dehydrocompounds of Formulae V and VI:

2-(3,4-Dihydroxybenzyl)-5-[2-(4-chlorophenyl)ethyl]pyrrolidine

2-(3,4-Dihydroxybenzyl)-5-[2-(4-fluorophenyl)ethyl]pyrrolidine

2-(3,4-Dihydroxybenzyl)-5-(2-phenylethyl)pyrrolidine

2-(3,4-Dimethoxybenzyl)-6-[2-(4-methoxyphenyl)ethyl]piperidine

2-(3,4-Dihydroxybenzyl)-6-[2-(4-hydroxyphenyl)ethyl]piperidine

2-(3,4-Dihydroxybenzyl)-6-[2-(4-chlorophenyl)ethyl]piperidine

2-(3,4-Dihydroxybenzyl)-6-[2-(4-fluorophenyl)ethyl]piperidine

2-(3,4-Dihydroxybenzyl)-6-(2-phenylethyl)piperidine

2-(4-Hydroxybenzyl)-5-[2-(4-hydroxyphenyl)ethyl]pyrrolidine

2-(3,4-Dihydroxybenzyl)-5-[2-(4-trifluoromethylphenyl)ethyl]pyrrolidine

2-(3,4-Dihydroxybenzyl)-6-[2-(4-chlorophenyl)ethyl]piperidine

2-(3,4-Dihydroxybenzyl)-6-[2-(4-fluorophenyl)ethyl]piperidine

2-(3,4-Dihydroxybenzyl)-6-(2-phenylethyl)piperidine

2(4-Hydroxybenzyl)-6-[2-(4-hydroxyphenyl)ethyl]piperidine

2-(3,4-Dihydroxybenzyl)-6-[2-(4-trifluoromethylphenyl)ethyl]piperidine

2-[2-Hydroxy-3(3,4-dihydroxyphenyloxy)propyl]-6-[2-(4-hydroxyphenyl)ethyl]piperidine

2-[2-Hydroxy-3-(3-fluoro-4-hydroxyphenyloxy)propyl]-6-[2-(4-hydroxyphenyl)ethyl]piperidine

We claim:
 1. A method for treating hypertension, which comprisesadministering to a patient in need of said treatment a therapeuticallyeffective amount for treating hypertension of a composition comprisingin combination with a pharmaceutically acceptable carrier a compound ofthe formula: ##STR16## or a pharmaceutically acceptable acid additionsalt thereof wherein, Z and Y are each alkylene containing one to aboutfive carbon atoms in the principal chain or said alkylene substitutedwith OH, or alkanoyloxy;each of R₁, R₂ and R₃ is independently H, alkyl,halo, alkoxy, alkylsulfinyl, alkylmercapto, cyano, carboxy, carbalkoxy,sulfamoyl, trifluoromethyl, hydroxy, hydroxyalkyl, or lower-alkanoyloxy;or R₁ and R₂, when taken together, form a methylenedioxy or--O--CO--O--; Ar is ##STR17## wherein, R₁, R₂ and R₃ are as hereindescribed; and R is H, alkyl, cycloalkyl, alkenyl, alkynyl, carbalkoxy,or CONR₄ R₅ wherein each of R₄ and R₅ is H or alkyl; wherein the totalnumber of carbon atoms in each hydrocarbyl group is up to
 6. 2. A methodfor treating hypertension, which comprises administering to a patient inneed of said treatment a therapeutically effective amount for treatinghypertension of a composition comprising in combination with apharmaceutically acceptable carrier a compound of the formula: ##STR18##or a pharmaceutically acceptable acid addition salt thereof, wherein,each of R₁ and R₂ is independently H, alkyl, halo, alkoxy,alkylsulfinyl, alkylmercapto, cyano, carboxy, carbalkoxy, sulfamoyl,trifluoromethyl, hydroxy, hydroxyalkyl, or lower-alkanoyloxy; and R₁ andR₂, when taken together, form a methylenedioxy, or --O--CO--O--; R₆ isH, alkyl, halo, alkoxy, alkylmercapto, cyano, carboxy, carbalkoxy,sulfamoyl, trifluoromethyl, hydroxy, hydroxyalkyl, or lower-alkanoyloxy;wherein the total number of carbon atoms in each hydrocarbyl group is upto
 6. 3. A method for treating hypertension, which comprisesadministering to a patient in need of said treatment a therapeuticallyeffective amount for treating hypertension of a composition according toclaim 2 wherein said compound is ##STR19##
 4. A method for treatinghypertension, which comprises administering to a patient in need of saidtreatment a therapeutically effective amount for treating hypertensionof a composition comprising in combination with a pharmaceuticallyacceptable carrier a compound of the formula: ##STR20## wherein R₁, R₂and R₆ are independently hydroxy or alkanoyloxy, wherein the alkylportion of the alkanoyloxy contains up to 6 carbon atoms.